Brain, Behavior, and Immunity 30 (2013) S1S9

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Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

Brief Commentary

Psychoneuroimmunology and cancer: A decade of discovery, paradigm shifts,

and methodological innovations
Paige Green McDonald a,, Mary OConnell b, Susan K. Lutgendorf c,d,e,f
a
Basic Biobehavioral and Psychological Sciences Branch, Behavioral Research Program (BRP), Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute
(NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), United States
b
BRP, DCCPS, NCI, NIH, DHHS, United States
c
Department of Psychology, University of Iowa, United States
d
Department of Urology, University of Iowa, United States
e
Department of Obstetrics and Gynecology, University of Iowa, United States
f
Holden Comprehensive Cancer Center, University of Iowa, United States

a r t i c l e i n f o a b s t r a c t

Article history: This article introduces the supplement Advances in Cancer and Brain, Behavior, and Immunity and outlines
Available online 16 January 2013 important discoveries, paradigm shifts, and methodological innovations that have emerged in the past
decade to advance mechanistic and translational understanding of biobehavioral inuences on tumor
Keywords: biology, cancer treatment-related sequelae, and cancer outcomes. We offer a heuristic framework for
Biobehavioral research on biobehavioral pathways in cancer. The shifting survivorship landscape is highlighted, and
Psycho-oncology we propose that the changing demographics suggest prudent adoption of a life course perspective of can-
Tumor biology
cer and cancer survivorship. We note opportunities for psychoneuroimmunology (PNI) research to ame-
Cancer treatment
Cancer outcomes
liorate the long-term, unintended consequences of aggressive curative intent and call attention to the
critical role of reciprocal translational pathways between animal and human studies. Lastly, we briey
summarize the articles included in this compilation and offer our perspectives on future research
directions.
Published by Elsevier Inc.

1. Introduction
In 2002, the National Cancer Institute (NCI), in collaboration
with other Institutes and Centers of the National Institutes of
Health, convened a meeting of scientic experts to discuss seminal
research on behavioral, neural, endocrine, and immune system
interactions in health and disease. To inform the development of
a biobehavioral research agenda in cancer control, knowledge
was extracted from contemporary studies of neuroimmune mech-
anisms of subjective experiences (e.g., stress, loneliness, and pain),
biological processes (e.g., circadian rhythmicity, sleep, wound heal-
ing, sickness behavior, and apoptosis), and disease outcomes (e.g.,
human immunodeciency virus, depression, and post-traumatic
stress disorder). Brain, Behavior, and Immunity published the Biolog-
ical Mechanisms of Psychosocial Effects on Disease supplement in
February 2003. This seminal volume captured state-of-the-science
reviews and commentaries by leading experts in psychoneuroim-
munology (PNI) and served as a catalyst for biobehavioral1 research
Corresponding author. Address: 6130 Executive Blvd, MSC 7363, Bethesda, MD
20892, United States. Tel.: +1 301 435 5037; fax: +1 301 435 7647.
E-mail addresses: mcdonald.paige@mail.nih.gov, pm252v@nih.gov (P. Green
McDonald).
1
For the purpose of this introduction, we use the terms biobehavioral and
psychosocial interchangeably.
conducted in a cancer context. In the decade prior to the NCI com-
missioned supplement, Brain, Behavior, and Immunity published only
12 cancer-relevant articles. Since the 2003 supplement, the journal
has featured 128 cancer-relevant papers that have generated 3361
citations (data from SCOPUS, retrieved November 1, 2012), relative
to 55 papers on PNI and cancer, published in other peer review jour-
nals during the same time period. These bibliometric data highlight
Brain, Behavior, and Immunity as a leading scholarly outlet for re-
search on the biology of psychological and social experiences and
the integrated mechanisms associated with cancer as a complex dis-
ease process. The current volume celebrates the 10-year anniversary
of the 2003 supplement. This collection of invited reviews and re-
search articles captures important discoveries, paradigm shifts, and
methodological innovations that have emerged in the past decade
to advance mechanistic and translational understanding of biobe-
havioral inuences on tumor biology, cancer treatment-related se-
quelae, and cancer outcomes.
2. Transition from cellular immunity in peripheral blood to
tumor-relevant measurements
Early clinical investigations focused almost exclusively on psy-
chosocial modulations of the humoral and cellular immune re-
sponse and, to some extent, on DNA repair (Andersen et al.,

0889-1591/$ - see front matter Published by Elsevier Inc.

http://dx.doi.org/10.1016/j.bbi.2013.01.003
S2 P. Green McDonald et al. / Brain, Behavior, and Immunity 30 (2013) S1S9
1994; Antoni, 2003; Kiecolt-Glaser and Glaser, 1999; Kiecolt-Gla-
ser et al., 2002). Women at an increased genetic risk for cancer
exhibited specic immune impairments and abnormalities in their
endocrine response to stress (Bovbjerg and Valdimarsdottir, 1993;
Dettenborn et al., 2005; Gold et al., 2003). Clinical studies docu-
mented associations between depression, social support, and natu-
ral killer cell activity in breast cancer patients (Levy et al., 1987;
Levy et al., 1985; Levy et al., 1990). Other research groups observed
distress/stress and social isolation-associated impairments in im-
mune function among breast, cervical and ovarian patients (Ander-
sen et al., 1998; Antoni et al., 2009; Lutgendorf et al., 2005; Nelson
et al., 2008; Sephton et al., 2009; Thornton et al., 2007); however,
the prognostic relevance of these associations remained uncertain
(Cohen and Rabin, 1998). Building on the clinical signicance of im-
mune cells in ascites (Lotzova et al., 1986; Lotzova et al., 1984) and
tumor-inltrating lymphocytes (Lai et al., 1996) in ovarian cancer,
Lutgendorf and colleagues observed signicant associations be-
tween psychosocial factors and the cellular immune response at
the tumor level in a clinical sample (Lutgendorf et al., 2005). This
study, among others, signaled an important contextual transition
for PNI studies of cancer, a transition aligned closely to advances in
cancer cell biology and emerging appreciation for target tissues
and the context in which tumors thrive (Marx, 2008).
3. Emergence of the tumor microenvironment
DeVita and Rosenberg (2012) recently chronicled signicant
discoveries and major events in cancer research since the founding
of the New England Journal of Medicine nearly 200 years ago (DeVita
and Rosenberg, 2012). Basic understanding of cancer biology has
matured substantially beyond Virchows observation of the cellular
origin of cancer and the view of tumors as insular masses of pro-
liferating cancer cells (p. 646, Hanahan and Weinberg, 2011). Pro-
gress has been led by milestones2 like observations from a
ploughman (Dell, 2006; Hart and Fidler, 1980; Paget, 1889), blood-
lines (Farrell, 2006; Folkman, 1971), environmental awareness
(Schuldt, 2006), and the hallmarks of cancer (Hanahan and Wein-
berg, 2000, 2011). Cancers have come to be seen as inherently com-
plex collections of heterogeneous pathologies that vary by tissue of
origin and constellation of genomic, proteomic, and metabolic alter-
ations (Fidler, 2003; Hanahan and Weinberg, 2000, 2011; Vogelstein
and Kinzler, 2004). Incipient mutated cells must acquire several bio-
logical capabilities to reach full malignancy, and several environ-
ments i.e., the primary, invasive and metastatic tumor
microenvironments are created during tumorigenesis (Hanahan
and Weinberg, 2011). In the case of solid tumors, commonly derived
from epithelial cells, these microenvironments provide a safe haven
for bidirectional communication between cancer cells and the tu-
mor-associated stroma. Cells that construct the microenvironments
include pericytes, cancer-associated broblasts, endothelial cells, lo-
cal and bone marrow-derived stromal stem and progenitor cells,
cancer stem cells, invasive cancer cells, and immune inammatory
cells (Albini and Sporn, 2007; Joyce, 2005; Joyce and Pollard, 2009;
Langley and Fidler, 2007; McAllister and Weinberg, 2010; McCawley
and Matrisian, 2001). Inammation, a seminal biological process in
the onset and progression of many diseases (Haroon et al., 2012;
Nathan, 2002), has emerged as an essential enabling process for tu-
mor growth and metastasis (Hanahan and Weinberg, 2011; Manto-
vani, 2009). Cytokines, chemokines, macrophages, and leukocyte
inltrates contribute to tumor progression by promoting invasion,
migration, and angiogenesis (Gonda et al., 2009; Mantovani et al.,
2008; Medrek et al., 2012; Pitroda et al., 2012; Solinas et al.,
2009). Truly, it takes a village of distinct cell types and signaling sys-
tems to support the tumor ecosystem.
2 3
See http://www.nature.com/milestones/milecancer/pdf/milecancer_all.pdf.
4. The central nervous system as a master regulator:
implications for cancer
Renewed appreciation of the landscapes that enable tumor
growth and metastatic dissemination inspire broader consider-
ation of the macro-physiological milieus that potentially shape
individual variability in the natural course of cancer and respon-
siveness to therapies (Castano et al., 2011; Schuller and Al-Wadei,
2010). We offer the following perspective (Fig. 1). The brain, as an
adaptive and dynamic synthesizer of experiential and perceptual
processes (Ganzel et al., 2010), can participate in the complex reg-
ulation of signaling systems used by the diverse array of cells and
structures to enable tumorigenesis. Experimental and clinical stud-
ies suggest that downstream activation of the sympathetic nervous
system and the hypothalamic-pituitary-adrenal axis exerts selec-
tive physiologic pressures that initiate molecular signaling path-
ways involved in DNA repair, angiogenesis, cell survival,
inammation, invasion, metastasis, and resistance to therapy
(Antoni et al., 2006; Cole and Sood, 2012; Hara et al., 2011; Lutgen-
dorf and Sood, 2011; Wu et al., 2004). Catecholamines (epineph-
rine, norepinephrine, dopamine) bind to a-adrenergic receptors
(a-ARs) and b-adrenergic receptors (b-ARs), and acetylcholine
binds to families of nicotinic (nAChRs) and muscarinic (mAChRs)
receptors found on tumor cells and stromal compartments within
the microenvironment (Schuller, 2008). Neuroendocrine receptor-
mediated signaling has the documented ability to regulate leuko-
cyte gene expression, molecular processes, and functional charac-
teristics of cells within microenvironments (Badino et al., 1996;
Cole and Sood, 2012; Lutgendorf et al., 2003; Lutgendorf et al.,
2009; Schuller and Al-Wadei, 2010). Examples of observed effects
include promotion of tumor cell growth, migration and invasive
capacity, and stimulation of angiogenesis by inducing production
of pro-angiogenic cytokines. Neuroendocrine hormones activate
oncogenic viruses and alter several aspects of immune function,
including antibody production, cell trafcking, and the production
and release of proinammatory cytokines (Glaser and Kiecolt-Gla-
ser, 2005; Webster Marketon and Glaser, 2008). Although not
explicitly reected in our conceptual schema, peripherally gener-
ated inammatory and other innate immune mediators can signal
back into the central nervous system, stimulate afferent nerves
that produce local cytokines, change neuronal function, and cause
sickness behaviors as an adaptive response to systemic pressures
(Dantzer and Kelley, 2007; Dantzer et al., 2012; Dantzer et al.,
2008; Irwin and Cole, 2011; Kelley et al., 2003; Miller et al.,
2008). Immune-to-brain communication cascades are thought to
undergird cancer and treatment-related symptoms such as fatigue,
depression, cognitive dysfunction, and sleep disturbance (Bower
et al., 2011; Dantzer et al., 2012; Lutgendorf and Sood, 2011; Miller
et al., 2008). Contemporary PNI remains poised to elucidate the
prevalence, impact, and etiologies of cancer-related physical and
affective sequelae at different phases of cancer survival (Bower,
2012; Dantzer et al., 2012; Haroon et al., 2012).
5. Shifting sands of survivorship
Advances in prevention, detection, and treatment (DeVita and
Rosenberg, 2012) continue to yield signicant declines in the inci-
dence of most cancers and death rates for all cancers combined
(Eheman et al., 2012; Siegel et al., 2012b). These trends, combined
with overall increases in life expectancy, have created a booming
[aging] cancer survivor population (p. 1996, Parry et al., 2011).
Siegel et al. estimated 13.7 million American cancer survivors
were alive in January 20123 (Siegel et al., 2012b). The majority
Number of survivors projected to increase to nearly 18 million by 2022.
 P. Green McDonald et al. / Brain, Behavior, and Immunity 30 (2013) S1S9
Fig. 1. Heuristic framework for research on biobehavioral risk factor inuences on clinical cancer course.
of this emergent demographic had far exceeded the 5-year survival
benchmark. Adolescent and young adult (AYA) survivors, diagnosed
at ages 15 to 29 years, have an 82% probability of survival 30 years
from diagnosis (Mertens et al., 2008). While this statistic is impres-
sive, seminal research by Oefnger, Lipshultz and others document
profound adverse long-term health-related outcomes following
exposure to highly aggressive curative intent therapies (Lipshultz
et al., 2012; Oefnger et al., 2006). Most notably relevant to PNI,
childhood cancer treatments are associated with late effects on
the cardiovascular, central nervous, endocrine, and immune sys-
tems. Further, survivors of adult, AYA, and pediatric cancers are
at risk for recurrence and subsequent malignancies. Relative to
the US population, survivors experience excess morbidity and mor-
tality due to cardiac and vascular abnormalities and pulmonary
complications (Choi et al., 2011; Mariotto et al., 2007; Oefnger
and Tonorezos, 2011; Siegel et al., 2012a; Valdivieso et al., 2012).
This landscape highlights an opportunity to use PNI paradigms to
understand cancer from a competing risk perspective in which
multiple factors concurrently affect risks for morbidity and mortal-
ity (Mell et al., 2010; Schairer et al., 2004). Although not consis-
tently observed (Zucca et al., 2012), age at diagnosis, general life
expectancy trends, and long-term physiological sequelae of treat-
ment exposure have converged to increase the prevalence of co-
morbidity or multimorbidity4 in a cancer context (Braithwaite
et al., 2012; Land et al., 2012; Patnaik et al., 2011; Ritchie et al.,
2011; Yood et al., 2012).
4
Multimorbidity is dened by the simultaneous existence of more than one
pathophysiologic condition or clinical entity (p. 371; Ritchie et al., 2011).
S3
6. Biobehavioral risk factors in the context of cancers as chronic
diseases
Early prevention, detection, and treatment advances have
shifted our conceptualization and management of most cancers
from acute to chronic disease models, which are often modulated
by psychosocial factors (Karelina and DeVries, 2011; Sullivan
et al., 2012; Williams, 2008; Wyman et al., 2012). This paradigm
shift further fuels our interest in psychosocial contributions to in-
tra-individual variability in cancer outcomes. Meta-analytic re-
views suggest stressful life experiences and depression are
associated with poorer survival and higher mortality across a di-
verse array of cancer types (e.g., breast, lung, head and neck, hepa-
tobiliary, lymphoid, and hematopoietic cancers) (Chida et al., 2008;
Pinquart and Duberstein, 2010; Satin et al., 2009). Prospective
endorsement of depressive symptoms, and cortisol slope were
associated with decreased survival in patients with metastatic re-
nal cell carcinoma (Cohen et al., 2012). Conversely, among women
with metastatic breast cancer, a decline in depressive symptoms
conferred survival benet (Giese-Davis et al., 2011). A recent
meta-analysis found the inuence of social relationships on mor-
tality comparable to risk conferred by tobacco and alcohol use. Fur-
ther, the social relationship risk for mortality exceeded risks
associated with physical activity (or lack thereof) and obesity
(Holt-Lunstad et al., 2010). Inammation often mediates associa-
tions between close relationships, depression, and chronic stress,
and health (Kiecolt-Glaser et al., 2010). Extending prior cross-sec-
tional ndings of social support, depression and inammatory
gene expression associations, ovarian cancer patients with a great-
er sense of social attachment had a lower likelihood of death (Lut-
gendorf et al., 2012). Lastly, perceived social isolation or loneliness
S4 P. Green McDonald et al. / Brain, Behavior, and Immunity 30 (2013) S1S9
predicts morbidity and mortality risk across different age groups
(Perissinotto et al., 2012; Udell et al., 2012).
7. Bioecological perspective of cancer and cancer survivorship
These data highlight the potential utility of life course/life span
or bioecological perspectives of cancer and cancer survivorship.
Most models of mortality and survival rely on tumor characteris-
tics and treatment exposure as prognostic indicators (Merletti
et al., 2011; Ward et al., 2004; Wei et al., 2010). Tumors develop
within microenvironments, yet cancers develop within a person
nested within several environmental contexts. Colditz and Wei
(2012) assert that traditional projections of cancer mortality fail
to account adequately for multilevel interactions and reciprocity
among biologic pathways, physical/built environment, and social/
behavioral factors (Colditz and Wei, 2012). Models that dynami-
cally capture exposure to multiple risk and protective factors, cer-
tain to have pleiotropic effects across and within time and levels of
analysis (Evans and Kim 2010), promise to reveal greater under-
standing of individual- and population-level differences in cancer
risk and outcome (Gehlert et al., 2008; Hiatt and Breen, 2008; War-
necke et al., 2008). Inequalities in cancer incidence, mortality, and
survival by race/ethnicity and socioeconomic status prevail5
(Chang et al., 2012; Merletti et al., 2011; Ward et al., 2004). A grow-
ing literature denes the biology of [social] disadvantage and early
adversity and offers tenable hypotheses and mechanistic pathways
as explanations for disparities in health and disease outcomes across
the lifespan (Adler and Stewart, 2010; Boyce et al., 2012; Kelly-Irving
et al., 2012). We use this platform to encourage deliberate invest-
ment in research on biopsychosocial mechanisms associated with
persistent disparities in cancer outcome (Parente et al., 2012).
8. Animal models of human disease: powerful tools for
elucidation of mechanisms
Use of correlation studies to support weight of the evidence
has been a prevalent criticism levied against PNI studies of cancer.
However, within the last decade, growing availability of transgenic
and knockout mouse models of human cancer provides opportuni-
ties to understand how PNI-type interactions may modulate the
molecular biology of cancer. Orthotopic and human tumor xeno-
graft models more accurately recapitulate the dynamics of human
cancer in vivo (Talmadge et al., 2007). Biologically sophisticated
animal models of human cancer provide a context for experimental
manipulation of psychosocial factors, such as environmental
enrichment (Cao et al., 2010), isolation (Hermes and McClintock,
2008), stress (Sheridan et al., 2004; Thaker et al., 2006), and
depression (Lamkin et al., 2011). In addition, animal models ad-
vance the discovery of the consequent changes in neuronal struc-
ture and function, neuroendocrine and immune activity, and
peripheral biology that inuence tumor cells and their microenvi-
ronment. In this conceptualization, psychosocial factors set the
stage for a macroenvironment that can shape tumor microenvi-
ronments to be more or less favorable to tumor growth. This sys-
tems-approach highlights the interactions of networks of pro-
tumor and anti-tumor mechanisms, and underscores the multiple
processes involved in both biobehavioral contributions to tumor
growth, as well as in resistance to tumor growth. Such a broad,
5
Social ecological theory predominately guides the exploration of the fundamental
causes of disparities in health. A thoughtful and balanced reection of the relative
contributions of local, State, and Federal level policies, social and physical environ-
ments, and access to and quality of health services is beyond the scope of this
commentary and research contained in this volume. For recent reviews and
perspectives see; Colditz et al., 2012 and Esnaola and Ford, 2012.
integrative approach will be necessary for the next steps in re-
search that target both mechanisms and interventions.
9. Overview of invited reviews and empirical reports in
Advances in Cancer and Brain, Behavior, and Immunity
Scholars in PNI and related disciplines and in cancer research
were invited to author the papers contained in this volume. Reec-
tive of the decade that bore witness to the sequencing of the hu-
man genome, the Cole review highlights several conceptual and
methodological innovations that are transforming our knowledge
of neural and endocrine regulation of the cancer genome (Cole,
2013). Sood and colleagues review studies that have converged
to rene our understanding of sympathetic nervous system regula-
tion of pathways relevant to cancer growth and progression (Ar-
maiz-Pena et al., 2012). The nuanced and selective inuences of
neuroendocrine hormones on tumor cells, stromal cells and the
metastatic cascade have come into focus and are beginning to re-
veal new therapeutic opportunities. Volden and Conzen present a
complementary review of the inuence of glucocorticoid signaling
on tumor progression through cell context-specic transcriptional
networks (Volden and Conzen, 2012 1045). In the clinical context,
disruption of HPA rhythms, as indicated by diurnal cortisol slopes,
predicted early metastatic breast cancer mortality (Sephton et al.,
2000). Sephton and colleagues, as reported in this volume, repli-
cate those ndings in a small sample of lung cancer patients fol-
lowed for a median of 4 years from date of diagnosis (Sephton
et al., 2012). Volden and Conzen foreshadow emerging interest in
stress regulation of epithelial cancer biology through metabolic
pathways and energy regulators such as insulin, leptin, ghrelin,
and adiponectin (Cao and During, 2012; Williams et al., 2009).
Convergence of animal models and human correlative studies
led Neeman and Ben-Eliyahu to identify catecholamine and prosta-
glandin-mediated immunosuppression as a perioperative risk fac-
tor for cancer recurrence and metastasis (Neeman and Ben-
Eliyahu, 2012). The authors advance a theoretical model that cap-
tures the cumulative risk and review mechanistic support for the
use of pharmacological blockade of key mediators during the per-
ioperative period. Sheridan and colleagues review the utility of a
mouse model of repeated social defeat to elucidate neural-immune
mechanisms in cancer (Powell et al., 2012). This review highlights
the role of myeloid-derived cells in stress-primed inammation, in
tissue remodeling in non-immune and immune organs, and in sup-
port of behavioral states experienced as cancer-associated sickness
behaviors (see reviews in this volume by Bower and Lamkin, 2012;
Costanzo et al., 2012; Irwin et al., 2012). The empirical paper by
Madden et al. examines the impact of social isolation on breast
cancer pathogenesis in adult severe combined immunodeciency
mice using a human breast cancer cell line known to express b-
ARs (Madden et al., 2012). The results raise implications of mild
vs. chronic stress exposure, timing of exposure during the life span
of experimental animals, and the need to capture transient shifts in
target cell populations. Further, the study supports the importance
of myeloid-derived suppressor cells and stress-associated leuko-
cyte recruitment as indicated by changes in macrophage popula-
tions in tumor and spleen, similar to that observed with social
disruption (SDR) stress paradigms (Engler et al., 2004; Powell
et al., 2012).
Bower and Lamkin identify two questions that direct contempo-
rary research on cancer-related fatigue, i.e., what are the neural
underpinnings of fatigue that are distinct from depression, and
what are the factors that contribute to inammation and fatigue
at different treatment phases (Bower and Lamkin, 2012)? The re-
view calls for established animal models of cancer-related fatigue,
attention to signal transduction pathways and downstream mark-
 P. Green McDonald et al. / Brain, Behavior, and Immunity 30 (2013) S1S9
ers of inammatory activation, prospective longitudinal studies of
fatigue to map time course and recovery, and exploration of mech-
anisms that might explain observations of symptom clusters. The
authors suggest early life stress as a plausible risk factor for inam-
mation that undergirds cancer-related fatigue. The empirical paper
by Witek-Jansek et al. in this volume explores whether childhood
adversity is associated with vulnerability for intense sustained
behavioral symptoms, including fatigue and depressive symptoms,
and quality of life and immune dysregulation (Witek Janusek et al.,
2012).
Irwin and colleagues describe the common presentation of sleep
disturbance and depression in cancer survivors (Irwin et al., 2012).
The authors outline a model in which sleep disturbance drives
alterations in inammatory biology, which result in of depressive
symptoms and in clinical depression for some. The model acknowl-
edges depression history and other psychosocial, biobehavioral,
and medical factors that might act as moderators. The Lutgendorf
laboratory contributes an analysis of associations between cortisol,
interleukin-6, depression, fatigue, and disability in ovarian cancer
patients followed prospectively from pre-surgical baseline to
one-year post surgery, and illustrates how chemotherapy acts to
normalize these biological markers (Schrepf et al., 2012).
Although challenges exist, the review by Costanzo et al. identi-
es opportunities to explore clinically signicant PNI relationships
in a hematopoietic stem cell transplantation context (HSCT) (Cost-
anzo et al., 2012). Improved understanding of the factors that mod-
erate timely immune recovery and optimal immune regulation
might confer improved short- and long-term outcomes for HSCT
recipients. Noted as challenges for PNI researchers working in a
HSCT context are the pace of change and evolution in HSCT medi-
cine and associated technical innovations. The secondary data
analysis by McGregor et al. investigating the effect of pre-trans-
plantation distress on white blood cell count among autologous
hematopoietic cell transplantation patients, highlights these chal-
lenges (McGregor et al., 2012).
Within the last decade, exercise has been established as an
effective adjuvant therapy to control adverse consequences associ-
ated with cancer treatment. Jones et al. comprehensively reviews
extant evidence linking exercise behavior, functional capacity/
exercise capacity, disease recurrence, and cancer-specic and all-
cause mortality (Betof et al., 2012). Further, the authors outline
host and tumor-related mechanisms underlying the exercise/t-
ness and prognosis relationship and review evidence from pre-clin-
ical animal models of cancer. This exciting work highlights exercise
as one critical component of energy balance inuences on cancer
etiology, progression, and outcome (Hursting et al., 2012).
This volume would not be complete without a balanced synthe-
sis of extant literature on psychological and physiological adapta-
tion and psychosocial interventions following a diagnosis of
cancer (Antoni, 2012). Antoni notes the opportunity to consider
outcomes beyond survival and disease recurrence, the importance
of determining optimal timing of interventions, acknowledgment
of cancers as different diseases, and the need to identify individuals
at high risk for poor outcomes. He discusses application of micro-
array and bioinformatic analyses (Cole, 2010; Cole et al., 2005) to
demonstrate that an intervention can causally inuence inamma-
tory and metastasis-regulated gene expression in circulating leuko-
cytes from early-stage breast cancer patients (Antoni et al., 2012).
Three empirical papers in this volume focus on cognitive dys-
function due to cancer treatment exposure in breast cancer sam-
ples (Ganz et al., 2012; Kesler et al., 2012; McDonald et al.,
2012). Ganz et al. conducted an interim cross-sectional analysis
of a prospective, longitudinal, observational cohort study to ex-
plore associations between proinammatory cytokines, cerebral
functioning, and chemotherapy exposure (Ganz et al., 2012). Sim-
ilarly, Kesler and colleagues investigated the correlations between
S5
hippocampal volume and peripheral cytokine levels in a sample of
breast cancer survivors nearly ve years post-chemotherapy expo-
sure (Kesler et al., 2012). The Kesler et al. and Ganz et al. papers re-
port associations between tumor necrosis factor-alpha (TNF-a) and
memory impairments. McDonald and colleagues replicate and ex-
tend prior work by their group and others (Kesler et al., 2011;
McDonald et al., 2010). Their current study reports chemother-
apy-associated structural brain changes in frontal regions that cor-
respond to concurrent perceptions of compromised executive
function (McDonald et al., 2012). We recognize that these studies
have limitations such as small samples sizes, discordance between
objective cognitive performance and subjective complaints, and, in
some cases, lack of pre/post-treatment and/or non-cancer control
comparisons. These limitations beg for prospective longitudinal
designs that facilitate pooling of data from different research
groups, harmonization of measures, and the use of advanced statis-
tical methods and modeling (Nelson and Suls, in press). Neverthe-
less, research presented by Ganz et al., Kesler et al., and McDonald
et al. nicely illustrates the nexus of brain, behavior, and
inammation.
10. Through the looking glass
This supplement synthesizes contemporary understanding of
PNI in a cancer context and suggests opportunities for further dis-
covery of mechanisms and development of interventions to im-
prove clinical cancer care. Multiple signaling pathways by which
the macroenvironment can inuence the tumor microenviron-
ment are identied, but many unanswered questions remain. For
example, numerous effects of catecholaminergic and glucocorti-
coid signaling on tumor growth and progression have begun to
be mapped, but it is likely that there are multiple downstream ef-
fects on tumor growth processes, many of which have not been
identied (for example, see Zappala et al., 2012). Hanahan and
Weinberg (2011), in an update to their classic paper, highlighted
10 hallmarks of cancer that are necessary for tumor growth and
progression. These include sustaining proliferative signaling; evad-
ing growth suppressors; avoiding immune destruction; enabling
replicative immortality; tumor-promoting inammation; activat-
ing invasion and metastasis, inducing angiogenesis; genome insta-
bility and mutation; resisting cell death; and deregulating cellular
energetics. The work highlighted in this issue describes how the
stress response can inuence the macroenvironment to support
these hallmarks.
In addition to effects on the tumor and microenvironment,
there are likely multiple upstream biobehaviorally modulated
pathways that may affect tumor growth, which will make produc-
tive targets for future investigation. These include the role of the
parasympathetic nervous system, of biobehaviorally sensitive neu-
ropeptides and hormones such as oxytocin, prolactin, growth hor-
mone, and prostaglandins, as well as a variety of metabolic
mediators (e.g. insulin growth factor-1, leptin, and ghrelin) that
are sensitive to biobehavioral pathways. Biobehavioral mediators
seldom work alone, and yet mechanistic research has focused on
investigation of discrete pathways for the sake of dening mecha-
nisms. However, to understand the relevant mechanisms, it will be
important to understand downstream effects of interconnected
pathways e.g., the synergistic effects on tumor dynamics of NE
and cortisol in chronic stress. We envision a complex web of sys-
temic pathways that inuence tumor growth and development at
multiple levels. This critical information will guide understanding
of whether therapies can be successful by blocking only adrenergic
signaling (as in use of beta-blockers), or whether adrenergic signal-
ing and prostaglandins must be jointly blocked (see Neeman and
Ben-Eliyahu, 2012), or whether adrenergic and glucocorticoid
S6 P. Green McDonald et al. / Brain, Behavior, and Immunity 30 (2013) S1S9
pathways must both be targeted. Understanding whether narrow
or broad targeting of therapies is clinically indicated is critical in
developing successful pharmacologic approaches. Behavioral inter-
ventions tend to be broad spectrum- targeting many overlapping
biobehavioral pathways; future research on behavioral interven-
tions may benet from analysis of which molecular pathways are
active.
Future research will also benet from parsing out effects of dif-
ferent biobehavioral states e.g. stress, depression, social isolation
to determine if there is one nal common pathway, or to what
extent there are discrete biological signatures of these different
psychological constructs. Molecular signatures of positive con-
structs also need further investigation. For example, does resilience
just mean less sympathetic activation or less hormonal and inam-
matory responsivity to stress, or does it mean greater parasympa-
thetic tone, or differential signaling of pathways such as those
involving oxytocin or dopamine? Likewise, it is not known whether
stress factors act in a relatively linear doseresponse fashion or
whether there are thresholds for stress/depression/social isolation
that determine physiological trajectories that will inuence the
clinical course of cancer. These kinds of data will help us better
understand who will most benet from behavioral or pharmaco-
logical interventions to reduce adrenergic signaling or stress re-
sponse states - for example, what levels of stress/distress are
necessary at the outset for an intervention to make a difference.
Moreover, the use of discrete interventions is useful for mechanis-
tic research purposes, but it is possible that multifaceted total life-
style interventions that address stress factors, as well as nutritional
and exercise lifestyle components, will be necessary to profoundly
impact cancer growth. To date, research on multimodal interven-
tions remains quite limited.
Additionally, the effects of biobehavioral pathways on recovery
from specic cancer treatments such as HSCT, adoptive immuno-
therapy, surgical recovery, are important frontiers for future work.
Understanding tumor and treatment effects on the central nervous
system are equally important. As reported by some of the papers in
this volume, we are just beginning to understand the relevant biol-
ogy in post-chemotherapy fatigue and cognitive difculties this
type of mechanistic understanding is critical before new treat-
ments can be developed and tested.
Future directions also include determination of what are the
most important intermediate outcome variables for biobehavioral
cancer research. In addition to overall survival and progression-
free survival, to what extent are gene signatures, metabolomics,
and epigenetic changes important outcomes for this work? The re-
search in this volume points to the dramatic discoveries that have
been made in the last decade to dene this eld. Future research
holds promise for discovery of novel biobehavioral signaling path-
ways that are relevant to cancer and a greater understanding of
behavioral, pharmacologic, and complementary interventions that
target these mechanisms.
In conclusion, we would be remiss if we did not thank lead
authors and their authorship teams for contributing scientic ad-
vances relevant to this volume. These individuals and many others
have worked quite tirelessly to improve methodological rigor,
establish causation as appropriate, collaborate in the spirit of
transdisciplinary team science, and move between different re-
search designs to test and conrm experimental and clinical nd-
ings. We thank the many scholars who engaged in the peer
review process to vet the invited mini-reviews and empirical pa-
pers that comprise this supplement. We acknowledge the inspira-
tion and contributions of the National Cancer Institute Network on
Biobehavioral Pathways in Cancer6 and the invaluable support of
6
See http://cancercontrol.cancer.gov/brp/bbpsb/ncintwk-biopthwys.html.
the National Cancer Institute Division of Cancer Control and Popula-
tion Sciences. Lastly, we thank the Brain, Behavior, and Immunity se-
nior editorial staff for their support of this special issue.
Conict of interest
The authors of this manuscript have nothing to declare.
Acknowledgments
Nicole Saiontz provided editorial support and Kate McNeil pro-
vided administrative management for the special issue. The Na-
tional Cancer Institute Network on Biobehavioral Pathways in
Cancer provided scientic consultation for the development of
the Figure. Figure illustration by Ethan Tyler. Figure design by Will
Bramlett.
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